Neurotransmitters and the Developing Nervous System
Carol Kellogg
My primary research interests are in developmental neurochemistry and neuropharmacology. In particular I am interested in the role that specific neurotransmitter molecules may have in the organization of neural function. By the early 1980s it had become evident that many neurotransmitter substances appear very early in brain development, before the appearance of synapses. It is now clear that several substances that will act as neurotransmitters in the mature brain have specific roles to play during brain development. I hypothesized that if these substances do play important developmental roles, then interference in their actions during brain development could have profound consequences on the course of brain development and on later brain function. Specific neurotransmitter systems are major targets for a variety of drugs and environmental chemicals and are also affected by altered physiologic states.
To test this hypothesis, I have examined how manipulation of the GABAA receptor influences development of the nervous system. GABA is the major inhibitory transmitter in the adult mammalian brain and is widely distributed in the brain. However, during early brain development, GABA depolarizes neurons, and trophic effects, mediated via the GABAA receptor, have been attributed to this substance. Interference with GABA systems during development might, therefore, be expected to have far-reaching consequences.
Using a variety of neurochemical, neuroanatomical, physiological and behavioral methods to evaluate the effects of early manipulation of the GABAA receptor on the nervous system and on behavior, we have found that drugs such as diazepam (Valium), which enhances the action of GABA at the receptor, do indeed have profound effects on a range of responses. Of great interest, many of the consequences of in utero exposure to GABAA receptor modulations do not become apparent until late in adolescence or adulthood, long after the drug has left the organism.
Several clinical neurobehavioral disorders (for example, bipolar disorder and schizophrenia) are now thought to be neurodevelopmental disorders. That is, even though the dysfunctions do not become manifest until late adolescence/young adulthood, the dysfunction relates to altered neural function brought about by a developmental insult at specific periods of development. While the clinical pathology supports such an hypothesis, there is no understanding of what the insults might be that can lead to certain disorders nor are the mechanisms that might link a developmental insult with later dysfunction understood.
Using the model that we have developed in rats, we hope to be able to identify the cascade of events that may be set in motion by a specific developmental insult. Only by knowing the mechanisms involved in mediating the impact of any insult (chemical, viral, or physiologic) can pharmacologic intervention be developed to counter the effect of such disorders. The growing awareness of neurodevelopmental disorders underscores the importance of understanding such mechanisms. Since many of the effects of in utero GABAA receptor manipulation are sex specific (as are many clinical behavioral disorders), we are currently evaluating possible interactions that may take place between GABA and other developmental trophic factors, for example, sex hormones and neurotrophins such as brain-derived neurotrophic factor.